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Structure of 39827-11-7 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With thionyl chloride In toluene at 20℃; for 8 h; Reflux
Benzo[b]thiophene-2-carbonyl chlorid[0104] Thianaphthene-2-carboxylic acid (356.42 mg, 2 mmol) was suspended in dry toluene (6 mL), thionyl chloride (4.4 mL, 60 mmol) and DMF (0.05 mL) were added at room temperature, and then the mixture was refluxed 8 h.4 The volatiles were removed at reduced pressure gave benzo[b]thiophene-2-carbonyl chloride as a yellow power. Purified by flash chromatography on silica gel, using ethyl acetate/hexane (1 :9) as eluent, give 3 as a white power (393.64 mg, 94.9percent). Spectral data were in accordance with those published.1H-NMR (300 MHz, CDCls): δ 8.31 (s, 1H), 7.04-7.89 (m, 2H), 7.60-7.46 (m, 2H. 13C NMR (300 MHz, CDC13): δ 161.14, 144.07, 138.05, 136.59, 135.89, 128.75, 126.68, 125.66, 122.91.
61%
With pyridine; thionyl chloride In tolueneReflux
Thionyl chloride (0.81 mL, 11.1 mmol) was added to a solution of benzo[b]thiophene-2-carboxylic acid 3 (0.4 g, 2.24 mmol), in pyridine (0.3 mL, 1.8 mmol) and toluene (15 mL, 14.1 mmol) at reflux. The reaction mixture was quenched in ice water and the toluene evaporated in vacuo. The acid chloride was extracted with distilled DCM (2.x.25 mL, 2.x.10 mL) and the combined organic extracts washed with distilled water (2.x.20 mL) and dried. The solvent was evaporated under reduced pressure to give a brown residue, which was purified using flash chromatography with DCM as the eluent to yield 11a17 (0.27 g, 61percent) as a colourless solid. 1H NMR (CDCl3, 300 MHz): δ 7.50 (m, 2H), 7.91 (m, 2H), 8.27 (s, 1H). 13C NMR: δ 123.1 (C3), 125.9 (C7), 126.9 (C4), 128.9 (C5 and C6), 136.1 (C2), 138.3 (C3a), 144.3 (C7) and 161.9 (CO). MS (CI+), m/z 197, 199 [MH+1, 35Cl, 37Cl].
1.1 g
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1 h;
To a 100-mL round-bottom flask was placed a solution of 1-benzothiophene-2-carboxylic acid (1.0 g,5.61 mmol)in DCM (30 mL) followed by the dropwise addition of oxalyl chloride (1.426 g,11.23 mmol) with stirring at 0°C. To the solution was added DMF (0.01 mL) then the reaction was stirred for 1H at a The solvent was removed under reduced pressure affording 1.1 g of 1-benzothiophene-2-carbonyl chloride as a yellow solid.
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 11, p. 3764 - 3767
[2] Patent: WO2012/99785, 2012, A2, . Location in patent: Page/Page column 25
[3] Tetrahedron Asymmetry, 2003, vol. 14, # 3, p. 339 - 346
[4] Organometallics, 2015, vol. 34, # 12, p. 3065 - 3071
[5] Journal of the American Chemical Society, 2005, vol. 127, # 43, p. 15010 - 15011
[6] Tetrahedron, 2011, vol. 67, # 36, p. 6895 - 6900
[7] Journal of Medicinal Chemistry, 1984, vol. 27, # 5, p. 570 - 576
[8] European Journal of Medicinal Chemistry, 2004, vol. 39, # 1, p. 85 - 97
[9] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 839 - 848
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 2074 - 2079
[11] Journal of Medicinal Chemistry, 2007, vol. 50, # 8, p. 1850 - 1864
[12] Patent: WO2006/91674, 2006, A1, . Location in patent: Page/Page column 87
[13] Patent: US5244893, 1993, A,
[14] Patent: US5304657, 1994, A,
[15] Heterocycles, 2008, vol. 75, # 8, p. 1913 - 1929
[16] Journal of Medicinal Chemistry, 2009, vol. 52, # 15, p. 4883 - 4891
[17] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7249 - 7257
[18] Chemical Communications, 2010, vol. 46, # 13, p. 2289 - 2291
[19] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 265 - 274
[20] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3581 - 3594
[21] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4189 - 4204
[22] Synthetic Communications, 2013, vol. 43, # 3, p. 337 - 344,8
[23] Synthetic Communications, 2013, vol. 43, # 3, p. 337 - 344
[24] Organic Letters, 2013, vol. 15, # 12, p. 3014 - 3017
[25] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 489 - 498
[26] Organic Letters, 2014, vol. 16, # 18, p. 4718 - 4721
[27] Organic Letters, 2017, vol. 19, # 23, p. 6332 - 6335
[28] European Journal of Organic Chemistry, 2015, vol. 2015, # 17, p. 3727 - 3742
[29] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6418 - 6426
[30] Patent: WO2016/100184, 2016, A1, . Location in patent: Paragraph 00691-00693
[31] Patent: KR2016/21163, 2016, A, . Location in patent: Paragraph 0890; 0892
[32] Patent: KR2015/25531, 2015, A, . Location in patent: Paragraph 0890; 0891; 0892
[33] Patent: CN103961348, 2016, B, . Location in patent: Paragraph 0039; 0051; 0052
[34] Organic Letters, 2017, vol. 19, # 12, p. 3091 - 3094
[35] Molecules, 2017, vol. 22, # 8,
[36] Patent: WO2017/62581, 2017, A1, . Location in patent: Paragraph 0313
[37] Synlett, 2017, vol. 28, # 19, p. 2594 - 2598
[38] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 4, p. 306 - 311
[39] Organic Letters, 2018, vol. 20, # 10, p. 3132 - 3135
[40] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4127 - 4135
[41] Chemical Communications, 2018, vol. 54, # 77, p. 10859 - 10862
[42] Patent: WO2018/231635, 2018, A1, . Location in patent: Paragraph 0045; 0047
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 3768,3769[2] Journal of the American Chemical Society, 1949, vol. 71, p. 2856,2857
5
[ 39827-11-7 ]
[ 89673-36-9 ]
Reference：
[1] Synthesis, 1983, # 11, p. 932 - 933
With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 20℃; for 8h;Reflux;
Benzo[b]thiophene-2-carbonyl chlorid[0104] Thianaphthene-2-carboxylic acid (356.42 mg, 2 mmol) was suspended in dry toluene (6 mL), thionyl chloride (4.4 mL, 60 mmol) and DMF (0.05 mL) were added at room temperature, and then the mixture was refluxed 8 h.4 The volatiles were removed at reduced pressure gave benzo[b]thiophene-2-carbonyl chloride as a yellow power. Purified by flash chromatography on silica gel, using ethyl acetate/hexane (1 :9) as eluent, give 3 as a white power (393.64 mg, 94.9%). Spectral data were in accordance with those published.1H-NMR (300 MHz, CDCls): delta 8.31 (s, 1H), 7.04-7.89 (m, 2H), 7.60-7.46 (m, 2H. 13C NMR (300 MHz, CDC13): delta 161.14, 144.07, 138.05, 136.59, 135.89, 128.75, 126.68, 125.66, 122.91.
61%
With pyridine; thionyl chloride; In toluene;Reflux;
Thionyl chloride (0.81 mL, 11.1 mmol) was added to a solution of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> 3 (0.4 g, 2.24 mmol), in pyridine (0.3 mL, 1.8 mmol) and toluene (15 mL, 14.1 mmol) at reflux. The reaction mixture was quenched in ice water and the toluene evaporated in vacuo. The acid chloride was extracted with distilled DCM (2×25 mL, 2×10 mL) and the combined organic extracts washed with distilled water (2×20 mL) and dried. The solvent was evaporated under reduced pressure to give a brown residue, which was purified using flash chromatography with DCM as the eluent to yield 11a17 (0.27 g, 61%) as a colourless solid. 1H NMR (CDCl3, 300 MHz): delta 7.50 (m, 2H), 7.91 (m, 2H), 8.27 (s, 1H). 13C NMR: delta 123.1 (C3), 125.9 (C7), 126.9 (C4), 128.9 (C5 and C6), 136.1 (C2), 138.3 (C3a), 144.3 (C7) and 161.9 (CO). MS (CI+), m/z 197, 199 [MH+1, 35Cl, 37Cl].
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane;
(+/-)-fralphan5-l-(Benzo[b]thiophene-2-carbonyl)-2-methyl-l,2,3,4-tetrahydro-quinoline-4- carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting benzo[b]thiophene-2-carbonyl chloride for 4-trifluoromethyl-benzoyl chlorided. Benzo[b]thiophene-2-carbonyl chloride was prepared by reaction of thianaphthene-2-carboxylic acid with oxalyl chloride and dimethylformamide in methylene chloride. The crude l-(benzo[b]thiophene-2-carbonyl)-2- methyl-l,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (1% methanol / methylene chloride) followed by purification via HPLC yielded (+/-)-/rans-2-methyl-l-(pyrimidine-5- carbonyl)-l,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (34%). 1H-NMR (CDCl3) delta: 1.02 - 1.18 (m, 6H), 1.65 - 1.75 (m, IH), 2.55 - 2.65 (m, IH), 3.60 - 3.70 (m, IH),3.80 (q, 2H), 5.05 - 5.15 (m, IH), 6.70 (d, IH), 6.80 - 7.00 (m, 3H), 7.20 -7.40 (m, 4H), 7.45 (s, IH),7.50 (d, 2H), 7.70 (d, IH), 7.80 (d, IH). MS m/z: 489/491 (M+l).
With thionyl chloride; In hexane;
To 57.5 g (0.324 mol) of benzothiophene-2-carboxylic acid in 600 ml of chlorobenzeno there are added dropwise with stirring at reflux temperature 57.8 g (0.468 mol) of thionyl chloride and, when the addition is complete, the mixture is stirred at reflux temperature until the evolution of gas has ceased. For working up, the reaction mixture is allowed to cool to room temperature and then concentrated in vacuo, the residue is stirred with n-hexane, and precipitate which has settled out is filtered off with suction and dried. 57.4 g (90% of theory) of benzothiophene-2-carboxylic acid chloride, which can be reacted further without additional purification, are obtained. STR11
With thionyl chloride;
(1) 1.0 g of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> was reacted with 2 ml of thionyl chloride under reflux overnight, and then excess thionyl chloride was distilled off under reduced pressure to obtain benzo[b]thiophene-2-carbonyl chloride as a solid product.
With thionyl chloride; for 2h;Reflux;
General procedure: Compounds 1, 2, 3, 4 and 5 were commercially available. Compounds 6, 7, 8, 9 and 10 were prepared from the corresponding carboxylic acid (9.18 mmol) and thionyl chloride (30 mL) with heating under reflux for 2 h. The thionyl chloride was removed in vacuo. The resulting acyl chloride was used without further purification.
With thionyl chloride; for 2h;Reflux;
General procedure: The heteroaryl acyl chlorides used in the synthesis of compounds 1b, 2b, 3b, 4b and 5b were commercially available. For compounds 6b, 7b, 8b, 9b and 10b, the chloride derivatives were prepared from the corresponding carboxylic acid (9.18 mmol) nd thionyl chloride (30 mL) with heating under reflux for 2 h. The thionyl chloride was removed in vacuo. The resulting acyl chloride was used without further purification.
With thionyl chloride;Reflux;
Compound 9a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide (328 mg, 1.5 mmol was addedfollowed by triethylamine (TEA; 0.42 mL, 3 mmol). The reactionmixture was stirred at room temperature. After the reaction wascompleted, the reaction mixture was diluted with CH2Cl2 andsequentially washed with water, 1 N HCl and saturated NaHCO3.The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane/ethyl acetate (EtOAc) = 4:1 to obtain 10a, (236 mg,76%) as white solid.
With thionyl chloride; at 60℃; for 2h;
A mixture of carboxylic acid in thionyl chloride (5 mL/mmol carboxylic acid) was stirred at 60 C for 2 hours. On completion, the solution was concentrated in vacuo to give the acid chloride, which was used directly without further purification. This material (1.1 eq) was added to a mixture of racemic amine (1 eq.) and triethylamine (2 eq.) in dichloromethane (3-5 mL/mmol racemic amine) at room temperature. The mixture was stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC to give racemic amide product. Following general procedure A, rac-1 was prepared from benzo[b]thiophene-2 -carboxylic acid and rac-A-104 (0.10 g, 0.65 mmol). The product was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini C 18 150x30 mm, particle size: 5 mupiiota; Mobile phase: 35-65% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give rac-1 (0.15 g, 73% yield) as a white solid. LCMS : (ES+) m/z (M+H)+ = 315.1.
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 50℃; for 0.333333h;
Benzo[b]thiophene-2-carboxylic acid (50 mg, 0.28 mmol)dichloromethane (3 mL) It was dissolved in thionyl chloride (SOCl2, 0.50 mL)and dimethylformamide (2 drops) It was added thereto, and was stirred for 20 minutes at 50C . Thereafter, the reaction mixture was concentrated under reduced pressure, dichloromethane (3 mL)after the diluted, quinolin-3-amine (50.0 mg, 0.347 mmol)and triethyl amine was added and stirred for a (100 mg, 0.988 mmol) and 15 hours at room temperature. Thin film chromatography (TLC) in verifying, new the spot location changes accordingly once created, reaction mixture of decompressing concentrated within, fraction is concentrated tosilica gel thin chromatography (preparative TLC, n/ethyl acetate = 2/1-hexanediol) for purifying the white solid thereby, a desired compound (23.0 mg, 27%) is obtained.
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 50℃; for 0.333333h;
Benzo [b] thiophene-2-carboxylic acid (50 mg, 0.28 mmol) and dichloromethane (3 mL) was dissolved in thionyl chloride (SOCl2, 0.50 mL) and dimethylformamide (2 drops) after the addition, the mixture was stirred for 20 minutes at 50 .Thereafter, the reaction mixture was concentrated under reduced pressure, dichloromethane (3 mL) and then diluted to, quinolin-3-amine (50.0 mg, 0.347 mmol) and triethylamine (100 mg, 0.988 mmol) was added to 15 at room temperature and and it stirred for hours. When the thin film check chromatography (TLC), when a new spot is generated, to give the mixture was concentrated under reduced pressure, and purified by silica gel preparative thin layer chromatography (preparative TLC, ethyl acetate / n- hexane = 2/1), the reaction mixture is object of a white solid to give the compound (23.0 mg, 27%).
With thionyl chloride; In dichloromethane; at 20℃;Inert atmosphere; Reflux;
General procedure: At low temperature conditions,The thionyl chloride was slowly added to the solution of compound 4 in anhydrous dichloromethane,After dripping,The reaction was returned to room temperature and refluxed under nitrogen.After the reaction is complete,Steaming all solvents,Then dissolved in anhydrous tetrahydrofuran or anhydrous dichloromethane,Compounds 3 and pyridine were added at low temperature,The reaction was transferred to room temperature and overnight.To the reaction system by adding water,And extracted three times with ethyl acetate,Combine organic phase,Washed three times with saturated sodium bicarbonate solution and saturated brine,Dried over anhydrous sodium sulfate and subjected to column chromatography to give compound 6.
With thionyl chloride;Reflux;
General procedure: Following a described procedure [24,42,43] with a few modifications, sodium borohydride wasslowly added to a suspension of selenium powder in water at room temperature or in ethanol, N2atmosphere and 0 C, and stirred until the formation of the typical colorless solution of NaHSe. Then,the corresponding aroyl or heteroaroyl chloride was added. Temperature and time of reaction varieddepending on the compounds. Methylation was achieved through the addition of methyl iodide(in excess). Purification was performed by several washings, recrystallization in different solvents orcolumn chromatography. In those cases where the acyl chloride was not available, it was formed bythe reaction of the corresponding carboxylic acid with SOCl2 for 1-8 h at reflux. Solvent was removedunder vacuum by rotatory evaporation, and the product was then washed three times with dry toluene,which was also eliminated by rotatory evaporation.
1.1 g
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h;
To a 100-mL round-bottom flask was placed a solution of 1-benzothiophene-2-carboxylic acid (1.0 g,5.61 mmol)in DCM (30 mL) followed by the dropwise addition of oxalyl chloride (1.426 g,11.23 mmol) with stirring at 0C. To the solution was added DMF (0.01 mL) then the reaction was stirred for 1H at a The solvent was removed under reduced pressure affording 1.1 g of 1-benzothiophene-2-carbonyl chloride as a yellow solid.
With thionyl chloride; for 2h;Reflux;
General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide.
With thionyl chloride;Reflux;
General procedure: Compound 28a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide(328 mg, 1.5 mmol was added followed by triethylamine (TEA;0.42 mL, 3 mmol). The reaction mixture was stirred at room temperature.After the reaction was completed, the reaction mixture was dilutedwith CH2Cl2 and sequentially washed with water, 1 N HCl and saturatedNaHCO3. The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane: Ethyl acetate (EtOAc)=4:1 to obtain 29a,(236 mg, 76%) as white solid.
With thionyl chloride; for 3h;Reflux;
To a dry 25mL round bottomed flask was added 44mg (0.25mmol) <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> and excess (5mL) thionyl chloride, and the resulting mixture held at reflux for 3h. The resulting benzo[b]thiophene-2- carbonyl chloride was then evaporated to dryness via rotavap in preparation for the next step.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;
1 General synthesis of intermediate d:
To a flask charged with D- or L-phenylglycinol (1.0 eq) and benzo[b]thiophene-2-carbonyl chloride (1.2 eq) was added anhydrous tetrahydrofuran and diisopropylethyl amine (2.5 eq). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted in ethyl acetate and washed with 2 X 0.5M HCl (aqueous) then 3 X brine. The organic layer was dried with sodium sulfate and concentrated to dryness. The resultant residue was purified by flash column chromatography (silica gel 0-20% methanol in dichloromethane).
benzo[<i>b</i>]thiophen-2-yl-[5-(benzo[<i>b</i>]thiophen-2-yl-hydroxy-methylene)-cyclopenta-1,3-dienyl]-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.9%
Stage #1: cyclopenta-1,3-diene With n-butyllithium In diethyl ether; hexane at 0℃; for 0.25h;
Stage #2: benzo<b>thiophene-2-carboxylic acid chloride In tetrahydrofuran; hexane at 20℃; for 1h;
Stage #1: methyl 1-methyl-1H-indole-3-carboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.833333h;
Stage #2: benzo<b>thiophene-2-carboxylic acid chloride In tetrahydrofuran at -78℃; for 4.5h;
10b 2-(Benzo[b]thiophene-2-carbonyl)-1-methyl-1H-indole-3-carboxylic acid methyl ester
To a stirred solution of methyl 1-methyl-indole-3-carboxylate (1.0 g, 3.54 mmol) in THF (20 mL) was added LDA (2.67 mL, 5.31 mmol) at -78° C. and stirred for 50 min. A solution of benzo[b]thiophene-2-carbonyl chloride (696 mg, 3.54 mmol) in THF (10 mL) was added. After stirring for 4.5 h, the reaction was quenched with brine and warmed to room temperature. The reaction mixture was extracted with EtOAc (50 mL*3). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography (Hexanes/EtOAc 3:1) gave 591 mg (48%) of compound 10b. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (m, 2H), 7.99 (m, 1H), 7.94 (s, 1H), 7.73 (m, 1H), 7.58 (m, 1H), 7.48-7.35 (m, 3H), 3.77 (s, 3H), 3.60 (s, 3H) ppm; MS (m/e) 350 (M+H).
Stage #1: 2-carbethoxyindole With tin(IV) chloride In dichloromethane at 0 - 20℃; for 0.5h;
Stage #2: benzo<b>thiophene-2-carboxylic acid chloride In nitromethane; dichloromethane at 20℃; for 40h;
14b
To a stirred solution of indole-2-carboxylic acid ethyl ester (1.0 g, 5.29 mmol) in CH2Cl2 (10 mL) was added tin (IV) chloride (5.82 mL, 5.82 mmol) at 0° C. The reaction was stirred at room temperature for 30 min. A solution of benzo[b]thiophene-2-carbonyl chloride (1.04 g, 5.29 mmol) in CH3NO3 (7.5 mL) was added and stirred for 40 h. The reaction was poured into an ice-water (30 mL) and warmed to room temperature. The reaction mixture was extracted with CH2Cl2 (50 mL*3). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography (Hexanes/EtOAc 3:1) to give 1.45 g (78%) of compound 13b. 500 mg of compound 13b was heated to reflux with H2NNH2-H2O in ethylene glycol (10 mL) for 1 h. After cooled to room temperature, the precipitate was collected by filtration, washed with EtOH, dried under vacuum to give 158 mg (35%) of Example 14b. 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 13.07 (s, 1H), 8.09-8.02 (m, 3H), 7.95 (m, 1H), 7.69 (m, 1H), 7.55-7.46 (m, 3H), 7.27 (m, 1H) ppm; MS (m/e) 318 (M+1).
S-(6,6-difluoro-5-methyl-5-hexenyl) benzo[b]thiophene-2-thiocarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With triethylamine In tetrahydrofuran at 20℃; for 1h;
13 Production Example 13; Production of compound (53) by the production method 2
Production Example 13; Production of compound (53) by the production method 2; To 10 ml of tetrahydrofuran were dissolved 0.25 g (1.5 mmol) of 6, 6-difluoro-5-methyl-5-hexene-1-thiol and 0.39 g (2.0 mmol) of benzo[b]thiophene-2-carbonylchloride, followed by the drop-wise addition of 0.30 g (3.0 mmol) of triethylamine at room temperature, followed by stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purifiedwith silica gel column chromatography (diisopropyl ether : hexane = 1 : 20) to obtain 0.39 g (yield: 80 %) of S-(6,6-difluoro-5-methyl-5-hexenyl) benzo[b]thiophene-2-thiocarboxylate.1H-NMR (CDCl3, TMS) δppm: 1.50-1.60 (5H, m), 1.65-1.75 (2H, m), 1.99-2.05 (2H, m), 3.13(2H, t), 7.38-7.49 (2H, m), 7.85-7.90 (2H, m), 8.05 (1H, s)
phosphoric acid mono-{2-[ (1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-phenyl-propyl} ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C9H14NO4P*ClH With sodium carbonate In water for 15h;
Stage #2: With hydrogenchloride In water at 0℃;
25.26 Example 25-26; phosphoric acid mono-{2- [ (1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-phenyl-propyl} ester
To a sodium carbonate solution (1 M, 1 mL) was added the aminophosphate 21b (68 mg, 0.254 mmol) and benzotiophene-2-carbonyl chloride (50 mg, 0. 254 mmol). After 15 h, it was acidified to pH-1 by addition of concentrated HCI solution at 0 C. Preparative HPLC purification afforded 20 mg (20% yield) of the title compound 25-26. 1H NMR (CD3OD) : δ 7.99-7. 86 (3H, m), 7.53-7. 15 (7H, m), 4.49 (1H, m), 4.10 (2H, m), 3.04 (2H, m); LCMS (ESP): 414 (M+Na+) ; 390 (M-H)-
20%
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C9H14NO4P*ClH With sodium carbonate In water for 15h;
Stage #2: With hydrogenchloride In water at 0℃;
25.26 Phosphoric acid mono-{2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-phenyl-propyl}ester
Example 25-26 Phosphoric acid mono-{2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-phenyl-propyl}ester To a sodium carbonate solution (1 M, 1 mL) was added the aminophosphate 21b (68 mg, 0.254 mmol) and benzothiophene-2-carbonyl chloride (50 mg, 0.254 mmol). After 15 h, it was acidified to pH~1 by addition of concentrated HCl solution at 0° C. Preparative HPLC purification afforded 20 mg (20% yield) of the title compound 25-26. 1H NMR (CD3OD): δ 7.99-7.86 (3H, m), 7.53-7.15 (7H, m), 4.49 (1H, m), 4.10 (2H, m), 3.04 (2H, m); LCMS (ESP): 414 (M+Na+); 390 (M-H)-.
With sodium carbonate; In water; at 0 - 20℃; for 15h;
To a 1 M Na2CO3 solution (5 mL) at 0 C was added <strong>[110117-84-5]D-3-fluorophenylalanine</strong> (0.5 g, 2.73 mmol) and 1-benzothiophene-2-carbonyl chloride (62 mg, 0.316 mmol). After 15 h at 20 C, the mixture was acidified by addition of ice-cold 5% HCl solution (10 mL). The suspension was extracted with methylene chloride (3x25 mL). The combined organic layers were dried over MgS04 and concentrated to yield 0.6 G of 87 as a white solid. The carboxylic acid 87 was dissolved in THF (5 mL). To the THF solution at 0 C was added 1 M borane in THF (1.31 mL). After 15 h at 25 C, a sat'd NaHCO3 solution (15 mL) was introduced. The suspension was stirred for 3 h and then extracted with methylene chloride (3x25 mL). The combined organic layers were washed with brine (2x25 mL), dried over Na2SO4, and concentrated. Purification by column chromatography (35% EtOAc in hexanes) gave 200 mg (22. 5% yield) of the compound 88. 1H NMR (CDCI3) : delta 7.84 (2H, m), 7.72 (1H, s), 7.41 (2H, m), 7.34-7. 25 (1H, m), 7. 11-6. 89 (3H, m), 6.41 (1H, br d, J=7.5 Hz), 4.37 (1 H, m), 3.77 (2H, m), 3.03 (2H, AB), 2.33 (1 H, br s).
To a 1 M Na2CO3 solution (5 mL) at 0 C. was added <strong>[110117-84-5]D-3-fluorophenylalanine</strong> (0.5 g, 2.73 mmol) and 1-benzothiophene-2-carbonyl chloride (62 mg, 0.316 mmol). After 15 h at 20 C., the mixture was acidified by addition of ice-cold 5% HCl solution (10 mL). The suspension was extracted with methylene chloride (3×25 mL). The combined organic layers were dried over MgSO4 and concentrated to yield 0.6 g of 87 as a white solid. The carboxylic acid 87 was dissolved in THF (5 mL). To the THF solution at 0 C. was added 1 M borane in THF (1.31 mL). After 15 h at 25 C., a sat'd NaHCO3 solution (15 mL) was introduced. The suspension was stirred for 3 h and then extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine (2×25 mL), dried over Na2SO4, and concentrated. Purification by column chromatography (35% EtOAc in hexanes) gave 200 mg (22.5% yield) of the compound 88. 1H NMR (CDCl3): delta 7.84 (2H, m), 7.72 (1H, s), 7.41 (2H, m), 7.34-7.25 (1H, m), 7.11-6.89 (3H, m), 6.41 (1H, brd, J=7.5 Hz), 4.37 (1H, m), 3.77 (2H, m), 3.03 (2H, AB), 2.33 (1H, br s).
phosphoric acid mono-{2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-pyridin-3-yl-propyl} ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C8H13N2O4P With sodium carbonate In water for 15h;
Stage #2: With hydrogenchloride In water at 0℃;
25.38 Example 25-38; phosphoric acid mono-{2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-pyridin-3-yl-propyl} ester
To a sodium carbonate solution (1 M, 1 mL) was added the aminophosphate 21E (110 mg, 0.474 mmol), 1-benzothiophene-2-carbonyl chloride (93 mg, 0.474 mmol). After 15 h, it was acidified to pH-1 by addition of concentrated HCI solution at 0 C. Preparative HPLC purification afforded 25 mg (14% yield) of the title compound 25-38. 1H NMR (CD3OD) : δ 8.83 (1H, s), 8.71-8. 63 (1H, m), 8. 58-8. 46 (10H, m), 8. 02-7. 83 (4H, m), 7.44 (2H, m), 4.60 (1H, m), 4.17 (2H, m), 3.42-3. 13 (2H, m) ; HRMS (MALDI) calc for C17H18N2O5PS (M+H+) 393.0674 ; found 393.0681.
14%
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C8H13N2O4P With sodium carbonate In water for 15h;
Stage #2: With hydrogenchloride In water at 0℃;
25.38 Phosphoric acid mono-{2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-pyridin-3-yl-propyl}ester
Example 25-38 Phosphoric acid mono-{2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-pyridin-3-yl-propyl}ester To a sodium carbonate solution (1 M, 1 mL) was added the aminophosphate 21e (110 mg, 0.474 mmol), 1-benzothiophene-2-carbonyl chloride (93 mg, 0.474 mmol). After 15 h, it was acidified to pH~1 by addition of concentrated HCl solution at 0° C. Preparative HPLC purification afforded 25 mg (14% yield) of the title compound 25-38. 1H NMR (CD3OD): δ 8.83 (1H, s), 8.71-8.63 (1H, m), 8.58-8.46 (10H, m), 8.02-7.83 (4H, m), 7.44 (2H, m), 4.60 (1H, m), 4.17 (2H, m), 3.42-3.13 (2H, m); HRMS (MALDI) calc for C17H18N2O5PS (M+H+) 393.0674; found 393.0681.
phosphoric acid mono-[2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-(2,3-difluoro-phenyl)-propyl] ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C9H12F2NO4P*ClH With sodium carbonate In water for 15h;
Stage #2: With hydrogenchloride In water at 0℃;
67 Example 67; phosphoric acid mono-[2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-(2,3- difluoro-phenyl)-propyl] ester
To a sodium carbonate solution (1 M, 5 mL) was added the aminophosphate 65 (199 mg, 0. 656 mmol) and benzo[b]thiophene-2-carbonyl chloride (129 mg, 0.656 mmol). After 15 h, it was acidified to pH 1 by the addition of 1 M HCI solution at 0 C. Preparative HPLC purification afforded 75 mg (27% yield) of the title compound 67.'H NMR (CD3OD) : δ 7.73-7. 62 (3H, m), 7.23-7. 15 (2H, m), 6.95-6. 78 (3H, m), 4.42-4. 29 (1H, m), 3.97-3. 82 (2H, m), 2.98 (1H, dd, J=13. 97,4. 91 Hz), 2. 80 (1H, dd, J=13. 98, 10. 20 Hz) ; LCMS : 426. 0 (M-H-) ; Elemental Analysis for (C18H16F2NO5PS. 0.20H2O) calc: C 50.16, H 3.84, N 3.25 ; found : C 50.04, H 3.85, N 3.32.
27%
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C9H12F2NO4P*ClH With sodium carbonate In water for 15h;
Stage #2: With hydrogenchloride In water at 0℃;
67 Phosphoric acid mono-[2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-(2,3-difluoro-phenyl)-propyl]ester
Example 67 Phosphoric acid mono-[2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3-(2,3-difluoro-phenyl)-propyl]ester To a sodium carbonate solution (1 M, 5 mL) was added the aminophosphate 65 (199 mg, 0.656 mmol) and benzo[b]thiophene-2-carbonyl chloride (129 mg, 0.656 mmol). After 15 h, it was acidified to pH~1 by the addition of 1 M HCl solution at 0° C. Preparative HPLC purification afforded 75 mg (27% yield) of the title compound 67. 1H NMR (CD3OD): δ 7.73-7.62 (3H, m), 7.23-7.15 (2H, m), 6.95-6.78 (3H, m), 4.42-4.29 (1H, m), 3.97-3.82 (2H, m), 2.98 (1H, dd, J=13.97, 4.91 Hz), 2.80 (1H, dd, J=13.98, 10.20 Hz); LCMS: 426.0 (M-H-); Elemental Analysis for (C18H16F2NO5PS. 0.20H2O) calc: C, 50.16; H, 3.84; N, 3.25; found: C, 50.04; H, 3.85; N, 3.32.
With triethylamine In dichloromethane at 20℃; for 1h;
69 Alcohol 69
Amine 68 (1. 05 g, 5.72 mmol) was dissolved in CH2CI2 (60 mL). Triethylamine (0.88 mL, 6.30 mmol) was added, followed by benzo [b] thiophene-2-carbonyl chloride (1.12 g, 5. 72 mmol). The reaction was stirred at room temperature for one hour, and the solvent was removed in vacuo. The product was purified by flash column chromatography eluting with a gradient of 30-60% EtOAc/hexanes (Rf = 0.24 (50% EtOAc/hexanes) to give 1.87 g (91%0 of a white solid 69. 1H NMR (DMSO-d6) : δ 1.68-1.75 (m, 2H), 2.87 (d, 2H, J=7. 0 Hz), 3.43-3.52 (m, 2H), 4.20-4.27 (m, 1H), 4.42 (t, 1H, J=5. 1 Hz), 6.94-7.00 (m, 1H), 7.03-7.08 (m, 2H), 7.25-7.32 (m, 1H), 7.39-7.46 (m, 2H), 7.90- 8.01 (m, 2H), 8.05 (s, 1H), 8.50 (d, 1H, J=8.5 Hz); LCMS 344 (M+H).
91%
With triethylamine In dichloromethane at 20℃; for 1h;
69
Amine 68 (1.05 g, 5.72 mmol) was dissolved in CH2Cl2 (60 mL). Triethylamine (0.88 mL, 6.30 mmol) was added, followed by benzo[b]thiophene-2-carbonyl chloride (1.12 g, 5.72 mmol). The reaction was stirred at room temperature for one hour, and the solvent was removed in vacuo. The product was purified by flash column chromatography eluting with a gradient of 30-60% EtOAc/hexanes (Rf=0.24 (50% EtOAc/hexanes) to give 1.87 g (91%) of a white solid 69. 1H NMR (DMSO-d6): δ 1.68-1.75 (m, 2H), 2.87 (d, 2H, J=7.0 Hz), 3.43-3.52 (m, 2H), 4.20-4.27 (m, 1H), 4.42 (t, 1H, J=5.1 Hz), 6.94-7.00 (m, 1H), 7.03-7.08 (m, 2H), 7.25-7.32 (m, 1H), 7.39-7.46 (m, 2H), 7.90-8.01 (m, 2H), 8.05 (s, 1H), 8.50 (d, 1H, J=8.5 Hz); LCMS 344 (M+H).
78.1
To a solution of 2-aminonicotinic acid (91.1 g, 8.0 mmol), triethylamine (2.7 mL, 19.1 mmol) and acetone/H2O (3:1, 100 mL) was added 1-benzothiophene-2-carbonyl chloride (2.04 g, 10.4 mmol) at 0° C. The resulting solution was allowed to warm to rt and stir overnight. The volatile solvent was removed under reduced pressure and the aqueous solution was acidified with HCl (conc.). The resulting precipitate was filtered and then washed with EtOAc and dried under reduced pressure to afford the product. (1.2 g, 52%). NMR (DMSO): 11.7(1H, broad), 8.60(1H, m); 8.36(1H, s); 8.25(1H, d); 8.07(1H, d); 8.02(1H, d); 7.51(2H, m); 7.36(1H, m).
With dmap; triethylamine In dichloromethane at 0 - 25℃; for 15h;
97
To a methylene chloride solution (5 mL) of the amine 96 (144 mg, 0.498 mmol) was added triethylamine (0.139 mL, 0.996 mmol), 4-(dimethylamino)pyridine (6 mg, 0.0498 mmol), and 1-benzothiophene-2-carbonyl chloride (123 mg, 0.623 mmol) at 0° C. After 15 h at 25° C., the mixture was diluted with methylene chloride (20 mL), washed with ice-cold HCl solution (1 M, 1×20 mL), sodium carbonate solution (1 M, 1×20 mL), and brine (1×20 mL). The solution was then dried (Na2SO4) and concentrated. The residue was purified by column chromatography (30-50% EtOAc in hexanes) to give 150 mg (67% yield) of the compound 97 as a white solid. 1H NMR (CDCl3): δ 7.85-7.65 (3H, m), 7.33 (2H, m), 7.21-7.15 (1H, m), 7.03 (1H, d, J=7.7 Hz), 6.96 (1H, br d, J=9.9 Hz), 6.88 (1H, td, J=8.1, 1.9 Hz), 4.51 (1H, d, J=2.1 Hz), 4.16-3.97 (4H, m), 3.17 (1H, dd, J=12, 5.1 Hz), 2.91 (1H, dd, J=13.4, 8.9 Hz), 2.02 (1H, d, J=4.7 Hz), 1.98 (1H, d, J=5.3 Hz), 1.33 (3H, t, J=6.9 Hz), 1.73 (3H, t, J=7.1 Hz); LCMS (ESP): 450 (M+H+), 472 (M+Na+); 448 (M-H).
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; (S)-2-amino-4-methyl-pentanoic acid [1-(4-chloro-benzenesulfonyl)-3-hydroxy-azepan-4-yl]-amide With benzotriazol-1-ol In dichloromethane at 20℃;
Stage #2: In dichloromethane at 20℃; for 2h;
6.c
To a solution of the compound of Example 6b (0.14 g, 0.335 mmol) in CH2Cl2 (20 mL) was added benzo[b]thiophene-2-carboxylic acid (0.81, 0.50 mmol), 1 -hydroxy benzotriazole (0.77g, 0.569mmol), and P-EDC (0.67g, 1 mmol/g) in CH2Cl2 (10 mL). After shaking at room temperature overnight, the solution was treated with tisamine (0.446 g, 3.75 mmol/g). After shaking for another 2 hours, the solution was filtered and concentrated to yield the title compound as a white solid (122.2 mg, 65%). MS (ESI): 562.2 (M+H)+.
2-[(benzo[b]thiophene-2-carbonyl)-amino]-4-methyl-pentanoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-ethyl-N,N-diisopropylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran
130.a (a)
(a) N-benzo[b]thiophene-2-ylcarbonyl-L-leucine methyl ester Benzo[b]thiophene-2-carbonyl chloride (4.9 g, 25 mmol) was added to a stirred solution of L-leucine methyl ester (4.5 g, 25 mmol) and diisopropylethylamine (9 ml, 51 mmol) in DCM (200 ml). After stirring for 2 hours at room temperature, the mixture was poured into water and washed with brine and dried (MgSO4). Evaporation under reduced pressure afforded the title compound as a white solid, 7.6 g, 100% yield. 1H NMR δ(CDCl3, 250 MHz) 7.88-7.78 (m, 3 H), 7.44-7.38 (m, 2 H), 6.53 (d, 1 H, J=7.6 Hz), 4.91-4.82 (m, 1H), 3.78 (s, 3 H), 1.82-1.60 (m, 3 H), 1.00 (app t, 6 H, J=5.9 Hz).
4-amino-N-(S-leucine)-3,3-dimethoxytetrahydrofuran[ No CAS ]
4-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3,3-dimethoxytetrahydrofuran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium hydrogencarbonate In 1,4-dioxane; methanol; ethyl acetate
131.c a
c) 4-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3,3-dimethoxytetrahydrofuran, diastereomer 1 Saturated sodium bicarbonate solution (5 ml) was added to a solution of 4-amino-N-(S-leucine)-3,3-dimethoxytetrahydrofuran, diastereomer 1 (0.13 g, 0.5 mmol) in 1.4-dioxane (5 ml) followed by benzo[b]thiophen-2-ylcarbonyl chloride (0.39 g, 2 mmol). After 45 minutes, the mixture was added to ethyl acetate, washed with water, sodium bicarbonate solution and water. The organic solution was then dried (MgSO4) and evaporated to give a white solid (0.47 g). Chromatography on silica gel (CH2Cl2 containing MeOH 0-5% gradient) gave the title compound (0.18 g, 89%) as a white solid, 1H NMR δ(CDCl3) 7.88 (s, 1H), 7.74 (m, 3H), 7.34 (m, 2H), 7.18 (d, 1H, J=7.1 Hz), 4.82 (m, 1H), 4.38 (dd, 1H, J=6.4, 12.3 Hz), 4.21 (dd, 1H, J=6.5, 9.2 Hz), 3.78 (ABq, 2H, J=3.8, 9.8 Hz), 3.62 (dd, 1H, J=5.2, 9.1 Hz), 1.78 (m, 3H), 0.99 (s, 3H), 0.96 (s, 3H).
4-[3-(thianaphthene-2-carbonylamino)propylthio]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69.1%
With sodium hydrogencarbonate; triethylamine In dichloromethane
85.ii ii)
ii) Synthesis of 4-[3-(thianaphthene-2-carbonylamino)propylthio]pyridine To a solution of 1.15 g (7.56 mmol) of 4-(3-aminopropyloxy)pyridine and 1.27 ml (9.11 mmol) of triethylamine in 50 ml of methylene chloride, 1.49 ml (7.58 mmol) of thianaphthene-2-carbonyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.65 g of the desired compound (yield: 69.1%, pale yellow crystals). mp 127°-128.5° C. Anal. for C17 H16 N2 O2 S.0.2H2 O. Calcd.: C; 64.62, H; 5.23, N; 8.87. Found: C; 64.54, H; 5.20, N; 8.93. NMR (200 MHz, CDCl3) δ:2.18 (2 H,m), 3.70 (2 H, m), 4.15 (2 H, t, J=5.8 Hz), 6.66 (1 H, br.), 6.81 (2 H, dd, J=4.8, 1.6 Hz), 7.34-7.48 (2 H, m), 7.75-7.91 (3 H, m), 8.43 (2 H, dd, J=4.8, 1.6 Hz). IR (KBr)cm-1: 3370, 1635, 1590, 1570, 1535, 1505, 1280, 1210, 1195.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C10H10ClN3O2 With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
47
Example 47:; To an acetonitrile/water solution (3 mL/4 mL) of 46a (170 mg, 0.710 mmol) wwas added benzo[B]thiophene-2-carbonyl chloride (140 mg, 0.710 mmol) and sodium carbonate (263 mg, 2.49 mmol). The mixture was stirred at room temperature for overnight. It was then acidified with 1 M HCI. Solid was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 28% yield. 1H NMR (DMSO-d6): δ 12.78 (1 H, brs), 9.23 (1 H, d, J=7.92 Hz), 8.13 (1 H, s), 8.06-7.93 (2H, m), 7.59-7.41 (4H, m), 7.16 (1 H, dd, J=8.47, 1.88 Hz), 5.06-4.97 (1 H, m), 3.49 (1 H, dd, J=15.45, 6.03 Hz), 3.36 (1 H, dd, J=15.07, 8.10 Hz). LCMS (APCI): 400.0 (M+H+). Elemental Analysis for (C19H14CIN3O3S0.3H2O) calc: C 56.31, H 3.63, N 10.37; found: C 56.35, H 3.66, N 10.34.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C10H10ClN3O2 With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
61
Example 61 :; To an acetonitrile/water solution (3 mL/4 mL) of 60a (216 mg, 0.611 mmol) was added benzo[B]thiophene-2-carbonyl chloride (120 mg, 0.611 mmol) and sodium carbonate (227 mg, 2.14 mmol). The mixture was stirred at room temperature for overnight. It was then acidified with 1 M HCI. Solid was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 55% yield. 1H NMR (DMSO-d6): δ 12.80 (1 H, br), 9.23 (1 H, d, J = 7.8 Hz), 8.13 (1 H, s), 8.02-8.00 (1 H, m), 7.95-7.93 (1 H, m), 7.48-7.41 (3H, m), 7.21-7.19 (1 H, m), 7.12 (1 H, t, J = 7.8 Hz), 5.04-4.98 (1 H, m), 3.50 (1 H, dd, J = 15.2, 6.1 Hz), 3.37 (1 H, dd, J = 15.2, 8.3 Hz). LCMS (API-ES): 400.0 (M+H+). Elemental Analysis for (C19H14CIN3O3S) calc: C 57.07, H 3.53, 10.51 ; found: C 56.98, H 3.60, N 10.27.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C11H12ClN3O2 With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
78
Example 78:; To an acetonitrile/water solution (3 mL/4 ml_) of 78a (145 mg, 0.572 mmol) was added benzo[B]thiophene-2-carbonyl chloride (113 mg, 0.572 mmol) and sodium carbonate (212 mg, 2.00 mmol). The mixture was stirred at room temperature for overweekend. It was then acidified with 1 M HCI. Solid was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 30% yield. 1H NMR (CD3OD): δ 7.80-7.72 (3H, m), 7.38-7.27 (4H, m), 7.04 (1 H, dd, J = 8.7, 2.1 Hz), 4.56 (1 H, dd, J = 9.2, 4.7 Hz), 3.00 (2H, t, J = 7.5 Hz), 2.55-2.44 (1 H, m), 2.35- 2.22 (1 H, m). LCMS (APCI): 414.0 (M+H+). Elemental Analysis for (C2OH16CIN3O3S1 H2O) calc: C 55.62, H 4.20, 9.73; found: C 55.48, H 4.21 , N 9.60.
With sodium carbonate In water; acetonitrile at 25℃; for 15h;
81
Example 81; To a sodium carbonate solution (1 M, 1.5mL) was added the amino acid 80a (112mg, 0.319mmol), 1- Benzothiophene-2-carbonyl chloride (93mg, 0.48mmol) and acetonitrile (1.5ml_). The mixture was stirred at 25°C for 15h. Preparative HPLC purification provided 35mg of the title product (27% yield). 1H NMR (DMSO-Of6): δ 8.58 (1 H, d, J=8.1 Hz), 8.21 (1 H, s), 7.9-7.83 (3H, m), 7.68 (1 H, dd, J=8.6, 1.5Hz), 7.59 (1 H, dd, J=8.8, 4.3Hz), 7.48 (2H, m), 7.16 (1 H, t, J=9Hz), 4.75 (1H, m), 3.3-3.1 (2H, m), 2.65 (2H, d, J=7.0Hz). LCMS (APCI positive): 398 (M+H+); Elemental Analysis for (C2OH16N3O3FS1.81CF3COOH0.3H2O) calc: C 49.97, H 3.34, N 7.82; found: C 50.00, H 3.39, N 7.78.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C13H15FN2O2 With sodium hydroxide; water In acetonitrile at 20℃; for 4h;
Stage #2: With hydrogenchloride In water; acetonitrile
108
Example 108; EPO To an acetonitrile/water solution (3 mL/3 ml_) of 103d (187 mg, 0.748 mmol) were added benzo[B]thiophene-2-carbonyl chloride (162 mg, 0.823 mmol), and sodium hydroxide (120 mg, 2.99 mmol). The mixture was stirred at room temperature for 4 hours. It was acidified with 1 M HCI and diluted with ethyl acetate (40 ml_). The ethyl acetate solution was washed with water (40 mL) and brine (20 mL), dried with Na2SO4 and concentrated. After column chromatography (50-100% ethyl acetate in hexane) and prep. HPLC purification, the title compound was obtained in 59% yield. 1H NMR (DMSO-d6): δ 12.88 (1 H, br), 11.14 (1 H, s), 9.07 (1 H, d, J = 8.1 Hz), 8.15 (1 H, s), 8.01-7.93 (2H, m), 7.46-7.35 (3H, m), 7.05 (1 H, dd, J = 10.1 , 1.8 Hz), 6.77-6.72 (1 H, m), 6.25 (1 H, s), 4.80-4.74 (1 H, m), 3.30-3.20 (2H, m). LCMS (APCI): 383.0 (M+H+). Elemental Analysis for (C20H15FN2O3S^O.1 H2O) calc: C 62.52, H 3.99, N 7.29; found: C 62.15, H 3.94, N 7.65.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 3.5h;
146
Example 146:; EPO 146To a dichloromethane solution (5 mL) of 143 (145 mg, 0.580 mmol) was added benzo[B]thiophene-2- carbonyl chloride (171 mg, 0.870 mmol), triethylamine (176 mg, 1.74 mmol) and 4- (dimethylamino)pyridine (7 mg, 0.058 mmol). The mixture was stirred at room temperature for 3.5 hours. It was then evaporated. The residue was dissolved in ethyl acetate (30 mL). The ethyl acetate solution was washed with water (20 mL), cold 1 M HCI (20 mL), cold 5% sodium bicarbonate (20 mL) and brine (20 mL), dried with Na2SO4 and concentrated. After column chromatography (10-20% ethyl acetate in hexane), the title compound was obtained in 94% yield.1H NMR (CDCI3): δ 7.66-7.56 (3H, m), 7.26-7.15 (1 H, m), 7.03-6.95 (1 H, m), 6.72-6.61 (2H, m), 4.89- 4.80 (1 H, m), 4.14-3.99 (2H, m), 3.27-3.18 (2H, m), 1.13-1.01 (3H, m). LCMS (API-ES): 411.1 (M+H+).
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; 3-(1H-benzoimidazol-2-yl)-alanine With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
11
Example 11 :; To an acetonitrile/water solution (4 ml_/5 ml_) of 9 (236 mg, 0.977 mmol) was added benzo[B]thiophene-2-carbonyl chloride (192 mg, 0.977 mmol) and sodium carbonate (362 mg, 3.42 mmol). The mixture was stirred at room temperature for overnight. It was then acidified with 1 M HCI. Solids was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 81% yield. 1H NMR (DMSO- d6): δ 12.57 (1 H, brs), 9.16 (1 H, d, J=7.83 Hz), 8.06 (1 H, s), 7.95 (1 H, d, J=7.33 Hz), 7.89 (1 H, d, J=8.59 Hz), 7.45-7.33 (4H, m), 7.08-7.02 (2H, m), 4.93 (1 H, dd, J=15.92, 8.09 Hz), 3.41 (1 H, dd, J=15.41 , 6.06 Hz), 3.28 (1 H, dd, J=15.42, 8.34 Hz). LCMS (APCI): 366.1 (M+H+). Elemental Analysis for (C19H15N3O3S) calc: C 62.45, H 4.14, N 11.50; found: C 62.23, H 4.21 , N 11.48.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; 3-(2-benzimidazolyl)-D-alanine With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
14
Example 14:; To an acetonitrile/water solution (4 mL/5 mL) of 13a (213 mg, 0.882 mmol) was added benzo[B]thiophene-2-carbonyl chloride (173 mg, 0.882 mmol) and sodium carbonate (327 mg, 3.09 mmol). The mixture was stirred at room temperature overnight. It was then acidified with 1 M HCI. Solid was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 84% yield. 1H NMR (DMSO-c/6): δ 9.38 (1 H, d, J=7.84 Hz), 8.29 (1 H, s), 8.17 (1 H, d, J=8.59 Hz), 8.12 (1 H, d, J=6.32 Hz), 7.68-7.56 (4H, m), 7.31 -7.24 (2H, m), 5.16 (1 H, dd, J=15.92, 8.09 Hz), 3.63 (1 H, dd, J=15.16, 5.81 Hz), 3.51 (1 H, dd, J=15.41 , 8.33 Hz). LCMS (APCI): 366.0 (M+H+). Elemental Analysis for (C19H15N3O3S) calc: C 62.45, H 4.14, N 11.50; found: C 62.30, H 4.32, N 11.50.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C10H10FN3O2 With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
17
Example 17:; To an acetonitrile/water solution (3 ml_/4 mL) of 16a (223 mg, 0.859 mmol) was added benzo[B]thiophene-2-carbonyl chloride (169 mg, 0.859 mmol) and sodium carbonate (319 mg, 3.01 mmol). The mixture was stirred at room temperature overnight. It was then acidified with 1 M HCI. Solid was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 85% yield. 1H NMR (DMSO-D6): δ 9.27-9.16 (1 H, m), 8.13 (1H, s), 8.06-7.93 (2H, m), 7.52-7.40 (3H, m), 7.36-7.27 (1H, m), 7.03-6.93 (1H, m), 5.04-4.96 (1 H, m), 3.52-3.31 (2H, m). LCMS (APCI): 384.0 (M+H+). Elemental Analysis for (C19H14FN3O3S) calc: C 59.52, H 3.68, N 10.96; found: C 59.57, H 3.83, N 10.86.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; 3-(6-fluoro-1H-benzimidazol-2-yl)-D-alanine With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
19
Example 19:; To an acetonitrile/water solution (5 ml_/6 mL) of 18a (391 mg, 1.75 mmol) was added benzo[B]thiophene-2-carbonyI chloride (345 mg, 1.75 mmol) and sodium carbonate (649 mg, 6.13 mmol). The mixture was stirred at room temperature for overnight. It was then acidified with 1 M HCI. Solid was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 69% yield. 1H NMR (DMSO): δ 12.71 (1 H, br), 9.20 (1 H, d, J = 7.8 Hz), 8.11 (1 H, s), 8.02-8.00 (1 H, m), 7.96-7.94 (1 H, m), 7.48-7.40 (3H, m), 7.29 (1 H, dd, J = 9.6, 2.5 Hz), 6.99-6.93 (1 H, m), 5.00-4.93 (1 H, m), 3.45 (1 H, dd, J = 15.4, 5.8 Hz), 3.33 (1 H, dd, J = 15.4, 8.3 Hz). LCMS (APCI): 384.0 (M+H+). Elemental Analysis for (C19Hi4FN3O3S0.2H2O) calc: C 58.97, H 3.75, 10.86; found: C 58.94, H 3.72, N 10.87.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C10H11N3O2*ClH With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
2
Example 2:; To an acetonitrile/water solution (4 mL /5 mL ) of aminoacid 1a (296 mg, 1.23 mmol) was added benzo[B]thiophene-2-carbonyl chloride (241 mg, 1.23 mmol) and sodium carbonate (456 mg, 4.31 mmol). The mixture was stirred at room temperature for overnight. It was then acidified with 1M HCI. Solids were filtered and washed with water (2x) and ethyl acetate (2x) to give the title compound in 76% yield. 1H NMR (DMSO-D6): δ 9.17 (1 H, d, J=7.72 Hz), 8.06 (1 H, s), 7.99-7.85 (2H, m), 7.47- 7.32 (4H, m), 7.10-7.00 (2H, m), 4.94 (1H, dd, J=13.94, 8.10 Hz), 3.46-3.23 (2H, m). LCMS (AP-ESI): 366.2 (M+H+). Elemental Analysis for (C19H15N3O3S03.H2O) calc: C 61.54, H 4.24, N 11.33; found: C 61.57, H 4.23, N 11.21.
With methylamine In tetrahydrofuran; methanol; water
43.a Preparation of 2-(methylaminomethyl)benzothiophene
a) N-methyl benzothiophene-2-carboxamide To a stirred solution of 2.0 M methylamine in THF (60 mL) and THF (60 mL) was added dropwise at 0 °C a solution of benzothiophene-2-carbonyl chloride (10.8 g, 55 mmole) in THF (50 mL) over 15 minutes. After the addition the reaction was allowed to warm to RT then was concentrated under vacuum. Trituration with a cold solution of 4:1 H2O/methanol (50 mL), filtration, and drying under vacuum gave the title compound (10.35 g, 98%) as a white solid: MS (ES) m/e 191.9 (M + H)+.
N-(4-[(1S,2R)-2-({(tert-butoxycarbonyl)amino[(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-6-methylquinazolin-2-yl)-1-benzothiophene-2-carboxamide dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h;
Stage #2: N-((1R,2S)-2-[(2-amino-6-methylquinazolin-4-yl)-amino]cyclohexyl)-N',N''-bis(tert-butoxycarbonyl)guanidine In dichloromethane at 20℃; for 15h;
1.1 Example 1; N-{4-[((1S,2R)-2-[amino(imino)methyl]amino}cyclohexyl)amino]-6-methylquinazolin-2-yl}-1-benzothiophene-2-carboxamide dihydrochloride; Step 1; N-(4-[(1S,2R)-2-({(tert-butoxycarbonyl)amino[(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-6-methylquinazolin-2-yl)-1-benzothiophene-2-carboxamide dihydrochloride
Step 1 N-(4-[(1S,2R)-2-({(tert-butoxycarbonyl)amino[(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-6-methylquinazolin-2-yl)-1-benzothiophene-2-carboxamide dihydrochloride To a 604 mg of N,N-diisopropylethylamine in 4 ml of methylene chloride, 10 mg of 4-dimethylaminopyridine and 613 mg of benzo[b]thiophene-2-carbonylchloride were added, and the mixture was stirred for 60 minutes. To the mixture was added dropwise a solution of 800 mg of N-{(1R,2S)-2-[(2-amino-6-methylquinazolin-4-yl)amino]cyclohexyl}-N',N''-bis(tert-butoxycarbonyl)guanidine obtained in Reference Example 1 in 5 ml of methylene chloride, followed by stirring at room temperature for 15 hours. The reaction solution was mixed with water, extracted with methylene chloride and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:. methanol = 30:1) to obtain 890 mg of the desirable compound.
With triethylamine In ISOPROPYLAMIDE at 40℃; for 48h;
1.b3
(b3) Synthesis of methyl (2S)-3-(4-alkyl/aryl carbonyl/sulphonyl phenyl)-2- [methoxy(oxo)acetyl]amino}propanoate (compounds A 7 DME to Al 2 DME, BlJ)ME- B3_DME, B12_DME and ClJ)ME to C/ 1J)ME)Each reactive building block (see list below in Table 5) was dissolved in dimethylacetamide (1.5 ml) and H-D-tyrosine methyl ester (112.5 mg, 0.4 mmol) was added to each reaction. To these reactions was added triethylamine (55.6 μl, 0.4 mmol) and dimethylaminopyridine (catalytic quantitiy). The mixtures were then stirred and heated (40° C) for 48 hours. Each reaction was purified by Cl 8 reverse phase chromatography.Table 5
1.e3
(e3) (2S)-3-[4-Alkyl/arylcarbonyUsulphonylphenyl]-2-[(carboxycarbonyl) aminojpropanoic acid (compounds A7-A12, B1-B7, B12 and C1-C6) Each acid chloride or sulphonyl chloride (list below in Table 11) was dissolved in dimethylacetamide (1.5 ml), to each reaction was added D-tyrosine bis t-butyl ester (109.6 mg, 0.3 mmol). To these reactions was then added triethylamine (67 μl, 0.48 mmol) and dimethylaminopyridine (trace, catalytic amount). The reactions were left to stir at 400C overnight. The solvent was evaporated and dichloromethane added (1 ml) followed by trifiuoroacetic acid (1 ml) were added, the reactions were left stirring for two hours. The solvent was removed and the compounds purified by reverse phase chromatography (details below).Table 11
With pyridine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
N-(6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)benzo[b]thiophene-2-carboxamide[00173] A 200-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 6-fluoro-2-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.45 g, 13.7 mmol), methylene chloride (85 mL), and pyridine (3 mL) and cooled to 0 0C. To the resulting solution, benzo[b]thiophene-2-carbonyl chloride (2.7 g, 13.7 mmol) was. The reaction was warmed to room temperature and stirred for 1 h. After this time, aqueous HCl (IM, 50 mL) was added to the reaction. The separated aqueous layer was extracted with dichloromethane (2x 25 mL). The combined organics were washed with aqueous HCl (IM, 2 x 5OmL), water (1 x 5OmL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude white solid (5.6 g, 99% yield) was used in the next step without further purification.
With pyridine; In dichloromethane; at 0 - 20℃; for 1.0h;Inert atmosphere;
A 200-mL single-neck round-bottom flask equipped with a magnetic stirrer was purged with nitrogen, charged with <strong>[1227210-37-8]6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline</strong> (S8, 3.45 g, 13.7 mmol), methylene chloride (85 mL), and pyridine (3 mL). After cooling to 0 C, the resulting solution was added with benzo[b]thiophene-2-carbonyl chloride (2.7 g, 13.7 mmol). The reaction mixture was then warmed to room temperature and stirred for 1 h. Subsequently aqueous HCl (1M, 50 mL) was added to the reaction mixture. After separation, the aqueous layer was extracted with dichloromethane (2x 25 mL). Combined organic layers were washed with aqueous HCl (1M, 2 x 50 mL), water (1 x 50 mL) and brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The resulting crude white solid (5.6 g, 99% yield) was used in the next step without further purification.
Se-benzyl imidoselenocarbamate hydrobromide[ No CAS ]
[ 1255908-08-7 ]
Yield
Reaction Conditions
Operation in experiment
36%
With pyridine In chloroform at 20℃; for 48h;
4.1.3. General procedure for the synthesis of compounds 1-10a, 1-10b and 1-10c
General procedure: A solution of the corresponding acyl chloride 1-10 (9.18 mmol) in chloroform (25 mL) was slowly added dropwise to a stirred solution of compounds a-c (4.59 mmol) in dry chloroform (40 mL) and pyridine (5 mL). The mixture was stirred for 48 h at room temperature. Solvents were removed under vacuum by rotatory evaporation and the residue was treated with water (100 mL) and purified.
methyl N,N'-di(thianaphthene-2-ylcarbonyl)-imidothiocarbamate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With pyridine In chloroform at 20℃; for 48h;
4.1.3. General procedure for the synthesis of compounds 1-10a, 1-10b and 1-10c
General procedure: A solution of the corresponding acyl chloride 1-10 (9.18 mmol) in chloroform (25 mL) was slowly added dropwise to a stirred solution of compounds a-c (4.59 mmol) in dry chloroform (40 mL) and pyridine (5 mL). The mixture was stirred for 48 h at room temperature. Solvents were removed under vacuum by rotatory evaporation and the residue was treated with water (100 mL) and purified.
With triethylamine In 1-methyl-pyrrolidin-2-one at 80 - 120℃; for 0.0666667h; Microwave irradiation;
18
ER-825412-00: As depicted in Scheme 18 above, ER-824188-00 (50.0 mg, 0.134 mmol) and benzo[B]thiophene-2-carbonyl chloride (32.6 mg, 0.166 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O0C for 120 seconds in the microwave. The reaction was not complete by analytical LC/MS. The reaction was re-subjected to heating at 12O0C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825412-00 (45.2 mg, 63%) as a white solid.
Stage #1: indole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; Inert atmosphere;
Stage #2: benzo<b>thiophene-2-carboxylic acid chloride In N,N-dimethyl-formamide at -60 - 20℃; for 12h; Inert atmosphere;
4.2.11. (Benzo[b]thien-2-yl)(1H-indol-1-yl)methanone (12a)
Anhydrous DMF (10 mL) was syringed in to a flask containing sodium hydride (0.082 g, 3.51 mmol) under nitrogen and the solution cooled to 5 °C (ice bath) with stirring. Indole (0.16 g, 1.36) dissolved in dry DMF (10 mL) was then added and stirring maintained for 45 min between 0 and 5 °C. The reaction mixture was then warmed to room temperature and stirring continued for a further 45 min after which time the mixture was cooled to -60 °C (liquid nitrogen/chloroform). The acid chloride 11a (0.27 g, 1.37 mmol) dissolved in dry DMF (15 mL) was then added slowly and the mixture warmed to room temperature and stirring maintained over 12 h. After all the substrate had reacted, the solvent was concentrated in vacuo to give a brown solid residue. Distilled water (20 mL) was added to the flask containing the residue and the mixture stirred for 1 h, after which time it was extracted with DCM (2×25 mL). The aqueous layer was washed once with DCM (15 mL). The combined organic solvents were then dried and evaporated to give a brown oil, which solidified rapidly. The solid was purified by column chromatography (40% ethyl acetate/hexane) to give 12a (0.27 g, 71%) as a brown crystalline solid. Mp 44-47 °C. Rf 0.8 (40% ethyl acetate/hexane). νmax 1662 cm-1 (CO). 1H NMR (CDCl3, 300 MHz): δ 6.71 (d, J=3.6 Hz, 1H, H3), 7.28 (d, J=15.6 Hz, 1H, H2), 7.33-7.46 (m, 4H, H5; H6, H5'; H6'), 7.74 (d, J=3.9 Hz, 1H, H4), 7.90 (s, 1H, H3'), 7.93 (dd, J=3.45, 5.3 Hz, 2H, ArH-H4 and H7), 8.44 (dd, J=1.2, 2.6 Hz, 1H, H7). 13C NMR: δ 102.8 (C3), 111.2 (C7), 120.0 (C4), 120.9 (C6), 121.2 (C3'), 122.2-125.5 (C5, C6, C4'-C7'), 125.8 (C2), 130.4 (C3a) and 138.7 (C7a). MS (CI+), 278 [MH+1]; 161 (C9H5OS+).
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; AMN-2cis With N-ethyl-N,N-diisopropylamine In dichloromethane at 100℃; for 0.166667h; Microwave irradiation;
Stage #2: With sodium carbonate In dichloromethane
AMD-3cis
2',3',4',9'-Tetrahydro-N,N-dimethyl-4-(3-fluorophenyl)-2'-(benzothiophen-2-yl)carbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indole]-4-amine (cis-diastereoisomer) The spiroamine (AMN-2cis; 264 mg, 0.7 mmol) was suspended in DCM (7 ml) in a vessel suitable for microwaves, and benzo[b]thiophene-2-carbonyl chloride (239 mg, 1.21 mmol) and diisopropylethylamine (180 mg, 1.4 mmol) were added. The reaction mixture was irradiated for 10 min at 100° C. in a microwave (Initiator Eight, Biotage). When the reaction was complete (TLC monitoring), the reaction mixture was diluted with DCM (15 ml) and filtered. Saturated Na2CO3 solution (8 ml) was added to the mother liquor. After separation of the phases, the aqueous phase was washed twice more with DCM. The combined organic phases were dried over MgSO4 and concentrated in a rotary evaporator. The crude product was purified by column chromatography [silica gel 60; DCM/methanol (19:1)]. The product AMD-3cis was obtained in a yield of 125 mg (33%). 1H NMR (600 MHz, DMSO-d6) d ppm 1.63-1.79 (m, 2H) 1.83-1.93 (m, 2H) 1.95 (s, 6H) 2.60 (d, J=13.60 Hz, 2H) 2.65 (t, J=5.67 Hz, 2H) 2.78-2.94 (m, 2H) 4.08-4.22 (m, 2H) 6.92 (t, J=7.55 Hz, 1H) 6.99 (t, J=7.55 Hz, 1H) 7.16 (t, J=8.31 Hz, 1H) 7.23 (d, J=8.31 Hz, 1H) 7.26-7.36 (m, 3H) 7.44-7.54 (m, 3H) 7.95 (s, 1H) 8.03 (d, J=7.55 Hz, 1H) 8.07 (d, J=8.31 Hz, 1H) 10.66 (s, 1H)
With N-ethyl-N,N-diisopropylamine In toluene at 110℃; for 2h;
5.1.2.3. Ethyl 2-(4-(Benzo[b]thiophene-2-carboxamido)-2-benzoylphenylamino)-2-oxoacetate (6a)
General procedure: To a stirred solution of compound 5a (0.20 g, 0.64 mmol) dissolved in toluene (4 mL) at 110 °C was added benzo[b]thiophene-2-carboxachloride (0.19 g, 0.96 mmol) and DIEA (0.12 g, 0.96 mmol). The reaction mixture was heated for 2 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (80 mL) and saturated NaHCO3 aq (80 mL). The organic layer was separated and washed with water (80 mL × 1) and brine (80 mL × 1), and then dried over anhydrous Na2SO4. The crude product was obtained after concentration and recrystalized with EtOAc to afford compound 6a as yellow solid (0.21 g, 69%).
With N-ethyl-N,N-diisopropylamine In toluene at 110℃; for 2h;
5.1.2.3. Ethyl 2-(4-(Benzo[b]thiophene-2-carboxamido)-2-benzoylphenylamino)-2-oxoacetate (6a)
General procedure: To a stirred solution of compound 5a (0.20 g, 0.64 mmol) dissolved in toluene (4 mL) at 110 °C was added benzo[b]thiophene-2-carboxachloride (0.19 g, 0.96 mmol) and DIEA (0.12 g, 0.96 mmol). The reaction mixture was heated for 2 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (80 mL) and saturated NaHCO3 aq (80 mL). The organic layer was separated and washed with water (80 mL × 1) and brine (80 mL × 1), and then dried over anhydrous Na2SO4. The crude product was obtained after concentration and recrystalized with EtOAc to afford compound 6a as yellow solid (0.21 g, 69%).
With N-ethyl-N,N-diisopropylamine In toluene at 110℃; for 2h;
5.1.2.3. Ethyl 2-(4-(Benzo[b]thiophene-2-carboxamido)-2-benzoylphenylamino)-2-oxoacetate (6a)
To a stirred solution of compound 5a (0.20 g, 0.64 mmol) dissolved in toluene (4 mL) at 110 °C was added benzo[b]thiophene-2-carboxachloride (0.19 g, 0.96 mmol) and DIEA (0.12 g, 0.96 mmol). The reaction mixture was heated for 2 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (80 mL) and saturated NaHCO3 aq (80 mL). The organic layer was separated and washed with water (80 mL × 1) and brine (80 mL × 1), and then dried over anhydrous Na2SO4. The crude product was obtained after concentration and recrystalized with EtOAc to afford compound 6a as yellow solid (0.21 g, 69%); mp 228-230 °C; 1H NMR (DMSO-d6) δ (ppm): 11.39 (s, 1H, NH), 10.72 (s, 1H, NH), 8.34 (s, 1H, ArH), 7.99-8.14 (m, 5H, ArH), 7.66 (d, J = 7.2 Hz, 2H, ArH), 7.70 (t, J = 7.5 Hz, 1H, ArH), 7.56 (t, J = 7.5 Hz, 2H, ArH), 7.46-7.50 (m, 2H, ArH), 4.26 (q, J = 7.2 Hz, 2H, CH2), 1.28 (t, J = 7.2 Hz, 3H, CH3); HRMS (ESI): m/z, Calcd for C26H21N2O5S [M+H+]: 473.1166, Found 473.1165.
tert-butyl methyl{trans-4-[(3-pyridin-4-ylbenzyl)amino]-cyclohexyl}carbamate[ No CAS ]
tert-butyl (trans-4-[(benzo[b]thiophene-2-yl)carbonyl](3-pyridin-4-ylbenzyl)amino} cyclohexyl)methylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With dmap; triethylamine In dichloromethane at 20℃; for 16h; Inert atmosphere;
General procedure for preparing carbamates 9a, 9b, 9c, 9d, 9e, 9g, 9h, 9i, 9j, 9k, 9l, 9m and carboxylate 13a
General procedure: To a solution of acyl chloride (1.0 equiv, commercially available or prepared from the corresponding acid) and N,N-dimethylpyridin-4-amine (0.1 equiv) in dry CH2Cl2 was added a solution of carbamate (1.0 equiv) or carboxylate (1.0 equiv) and NEt3 (5.0 equiv) in dry CH2Cl2 at rt. The resulting solution was stirred at rt for 16 h (TLC control). The solvent was removed under reduced pressure and the crude product was purified by column chromatography using a sufficient mixture of n-hexane/acetone (v/v) as eluent.
4'-((1-methylpiperidin-4-yl)oxy)-[1,1'-biphenyl]-4-amine[ No CAS ]
N-(4'-((1-methylpiperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)benzo[b]thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With triethylamine In dichloromethane for 12h;
4.2.76.1 N-(4′-((1-methylpiperidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)benzamide (41a): general procedure for the synthesis of 41a-s, 43a-b, 45a-b, 47a-b and 49a-h
General procedure: Acid chloride 40a (50mg, 0.36mmol) was added to a solution of aniline 9c (50mg, 0.18mmol) and triethylamine (0.13mL, 0.94mmol) in anhydrous dichloromethane (5mL). After 12h, the solvent was removed and the residue was purified via column chromatography (SiO2, 10:1, CH2Cl2: methanol) to afford 41a as a white amorphous solid (51mg, 74%).
81%
With triethylamine In dichloromethane for 12h;
2 N-(4'-((1-methylpiperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)benzo[b]thiophene-2- carboxamide (47b):
N-(4'-((1-methylpiperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)benzo[b]thiophene-2- carboxamide (47b): Acid chloride 46b (0.36 mmol) was added to a solution of aniline 7 (0.18 mmol) and triethylamine (0.13 mL, 0.94 mmol) in anhydrous dichloromethane (5 mL). After 12 h, the solvent was removed and the residue was purified via column chromatography (SiO2, 10:1, CH2Cl2: methanol) to afford a white amorphous solid (81%). 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H, NH), 8.45 (s, 1H), 8.07 (dd, J = 7.4, 1.5 Hz, 1H), 8.05- 7.99 (m, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.53 - 7.46 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.68- 4.46 (m, 1H), 3.06- 2.96 (m, 2H), 2.85- 2.74 (m, 2H), 2.54 (s, 3H), 2.17- 2.03 (m, 2H), 1.91- 1.78 (m, 2H). 13C NMR (126 MHz, DMSO) δ 160.23, 156.09, 140.44, 140.04, 139.12, 137.50, 135.17, 132.39, 127.47, 126.34, 125.89, 125.39, 125.04, 122.83, 122.71, 120.58, 116.33, 69.70, 50.70, 43.47, 28.36. HRMS (ESI+) m/z: [M + H+] calcd for C27H27N2O2S 443.1793; found 443.1791
N-(3-bromopropyl)benzo[b]thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine In dichloromethane at 20℃;
5 5.1.1. N-(3-Bromopropyl)-3,5-dichlorobenzamide (29a)
General procedure: Compound 28a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide(328 mg, 1.5 mmol was added followed by triethylamine (TEA;0.42 mL, 3 mmol). The reaction mixture was stirred at room temperature.After the reaction was completed, the reaction mixture was dilutedwith CH2Cl2 and sequentially washed with water, 1 N HCl and saturatedNaHCO3. The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane: Ethyl acetate (EtOAc)=4:1 to obtain 29a,(236 mg, 76%) as white solid. Retention factor Rf=0.85 (n-hexane:EtOAc=1:1). Mp=98 °C. 1H NMR (300 MHz, CDCl3): δ 7.62 (d,J=1.8 Hz, 2H), 7.49 (s, J=1.8 Hz, 1H), 6.38 (s, 1H), 3.62 (q,J=6.4 Hz, 2H), 3.49 (t, J=6.3 Hz, 2H), 2.21 (quin, J=6.5 Hz, 2H).
325 mg
With triethylamine In dichloromethane at 20℃;
4 5.1.1. N-(3-Bromopropyl)-3,5-dichlorobenzamide (10a)
General procedure: Compound 9a (191 mg, 1 mmol) was refluxed in excess of thionyl chloride (3 mL) overnight. Excess of thionyl chloride was evaporated and the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide (328 mg, 1.5 mmol was added followed by triethylamine (TEA; 0.42 mL, 3 mmol). The reaction mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was diluted with CH2Cl2 and sequentially washed with water, 1 N HCl and saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. The obtained product was purified by column chromatography with n-hexane/ethyl acetate (EtOAc) = 4:1 to obtain 10a, (236 mg, 76%) as white solid.
(1R,4aS,E)-methyl 9-((2-aminoethoxy)imino)-6-bromo-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate[ No CAS ]
(1R,4aS,E)-methyl 9-(2-(benzo[b]thiophene-2-carboxamido)ethoxyimino)-6-bromo-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With potassium carbonate In acetonitrile at 20℃; for 3h; Inert atmosphere;
General procedurefor preparation of coMp ounds 8a-8z; 10-13.
General procedure: A mixture of the methylester 6a-d, 7 (0.216 mmol), K2CO3 (0.324 mmol) in CH3CN(25mL), the appropriate acyl chloride (0.26 mmol) wasadded under nitrogen atmosphere, stirred at rt for 3 h,the solvent was evaporated in vacuum. The residue was diluted with water. The whole was extracted with AcOEt for 3 times. The combined organic layer was washed with water, sat.brine, dried over Na2SO4. The crude mixture was purifiedby (n-hexane/AcOEt = 8:1) to afford 8a-z, 10-13.
(±)-N-(2,2-dimethylquinuclidin-3-yl)benzo[b]thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With triethylamine In dichloromethane at 20℃; for 2h;
1 Preparation of (+/-)-N-(2,2-dimethylquinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
A mixture of carboxylic acid in thionyl chloride (5 mL/mmol carboxylic acid) was stirred at 60 °C for 2 hours. On completion, the solution was concentrated in vacuo to give the acid chloride, which was used directly without further purification. This material (1.1 eq) was added to a mixture of racemic amine (1 eq.) and triethylamine (2 eq.) in dichloromethane (3-5 mL/mmol racemic amine) at room temperature. The mixture was stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC to give racemic amide product. Following general procedure A, rac-1 was prepared from benzo[b]thiophene-2 -carboxylic acid and rac-A-104 (0.10 g, 0.65 mmol). The product was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini C 18 150x30 mm, particle size: 5 μπι; Mobile phase: 35-65% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give rac-1 (0.15 g, 73% yield) as a white solid. LCMS : (ES+) m/z (M+H)+ = 315.1.
(1R,4aS,E)-methyl-9-((3-(benzo[b]thiophene-2-carboxamido)propoxy)imino)-6-bromo-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With potassium carbonate In acetonitrile at 20℃; for 3h; Inert atmosphere;
6.3. General procedure for preparation of compounds 3a-s
General procedure: A mixture of 3 (0.216 mmol), K2CO3 (0.324 mmol) in acetonitrile(25 mL), and the appropriate acyl chloride (0.26 mmol) was addedunder nitrogen atmosphere, stirred at rt for 3 h, the solvent wasevaporated in vacuum. The residue was diluted with water. Thewhole mixture was extracted with AcOEt for three times. Thecombined organic layer was washed with water, sat. brine, anddried over Na2SO4. The crude product was purified by columnchromatography using petroleum ether/AcOEt (2/1-5/1, v/v) aseluent to afford 3a-s.
4-[5-(2-hydroxyphenyl)-3,4-dihydro-2H-pyrazol-3-yl]-2,6-dimethoxyphenol[ No CAS ]
benzo[b]thiophen-2-yl-[5-(4-hydroxy-3,5-dimethoxyphenyl)-3-(2-hydroxyphenyl)-4,5-dihydropyrazol-1-yl]methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.67%
With pyridine In ethanol at 80℃; for 1h;
3.3. General Procedures for the Synthesis of Compounds b1-19
General procedure: Hydrazine hydrate (0.04 mol, 1.96 g) was added to a solution of compound a1 (0.01 mol,3.00 g) in ethanol (10 mL). The mixture was refluxed under stirring for 4 h, and the reactionmixture was subsequently poured onto crushed ice; the precipitate was filtered out, and productb1 was later crystallized from ethanol. Compounds b2-4 were synthesized following this procedure.Compounds b5-17 were prepared by treating compound b1 (0.01 mol, 3.14 g) with correspondingsubstituted benzoyl chloride or substituted benzenesulfonyl chloride (0.015 mol) at 80 °C in ethanolas solvent with pyridine as catalyst for 1 h to yield the final N-substituted targeted compounds.The N-phenyl-substituted pyrazolines b18 and b19 were prepared by direct cyclization of a1 and a5,respectively, with phenylhydrazine in the presence of TBAB as a catalyst [29].
With sodium hydrogen selenide In ethanol at 20℃; for 0.5h; Inert atmosphere;
3.2.3. General Procedure for Compounds 1-3, 5, 7, 10, 12 and 13
General procedure: Under N2 atmosphere, absolute ethanol (10 mL) was added to a mixture of NaBH4 (2.15 mmol)and selenium (2 mmol) cooled by an ice bath, with magnetic stirring. Although reaction of thesespecies occurs 1:1, a little excess of NaBH4 was added, due to the slow rate of decomposition of NaBH4in this solvent reported by Klayman et al. [42] When the typical colorless solution of NaHSe wasachieved, the ice bath was removed and the following reactions were carried out at room temperature.The acyl chloride was added and stirred for different amounts of time, depending on the reagents.Reaction was followed by TLC or IR. Before adding an excess of methyl iodide (1.5 mL), the mixturewas filtered. After discoloration (20 min-1 h), the mixture was filtered, and ethanol was eliminatedwith rotatory evaporation or the product was precipitated with water. Compounds were purifiedthrough recrystallization from different solvents or column chromatography.
2-(1-benzothiophene-2-amido)-3,5-dimethylbenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With sodium carbonate; In tetrahydrofuran; water; at 0℃; for 0.5h;
To a 100-mL 3-necked round-bottom flask was placed a solution of <strong>[14438-32-5]2-amino-3,5-dimethylbenzoic acid</strong> (0.973 g,5.89 mmol) in THF (20 mL) and a solution of Na2CO3 (1.79 g,16.73 mmol) in water (20 mL). This was followed by the dropwise addition of 1-benzothiophene-2-carbonyl chloride (1.1 g,5.59 mmol,as prepared above) in THF (20 mL) with stirring at 0C over 30 mm. The resulting solution was stirred for 1H at rt then the reaction was diluted with 20 mL of water and the pH was adjusted to 2 with aqueous 2N HC1.The resulting solution was extracted with EtOAc (3x30 mL) and the organic extracts were combined. The solution was washed with brine (2x20 mL),dried over anhydrous Na2SO4,and concentrated under reduced pressure affording 1 g (55%) of the title compound as a yellow solid. Mass Spectrum (LCMS,ESI neg): Calcd. for C18H16NO3S: 324.1 (M-H); Found: 324.
300 mg (0.581 mmol) of <strong>[3482-49-3]fusidic acid</strong> and 142 mg (1.161 mmol) of 4-dimethylaminopyridine (DMAP) were first weighed in a 50 mL magnetron-containing round bottom flask,Under nitrogen protection, measure 10 mL of ultra-dried anhydrous methylene chloride in a flask, and stir at room temperature under nitrogen for about 15 minutes until it is completely dissolved.0.94 mL (1.161 mmol) of pyridine was added via syringe, stirred for about 20 min at room temperature under nitrogen, and finally 0.34 mL (1.743 mmol) of benzothiophene-2-carbonyl chloride was added three times at room temperature under nitrogen protection. The reaction was stirred for 2 h.The end point of the reaction was checked by TLC (developer: dichloromethane:ethyl acetate=3:1, coloring agent: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio)=85:10:5:0.5), and the reaction was completed. The crude product of compound FA-E-16 was obtained by washing and extractive drying and the like, and purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate=6:1) to give compound FA-E-16, which The molecular structure is shown in Fig. 16. White solid, Rf = 0.37 (developer: dichloromethane:ethyl acetate = 3:1), yield: 68%.
methyl 3-(benzo[b]thiophen-2-yl)-3-oxo-2-phenylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: benzeneacetic acid methyl ester With n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran; hexane at -78℃; for 0.166667h;
Stage #2: benzo<b>thiophene-2-carboxylic acid chloride In tetrahydrofuran; hexane at -78 - 20℃;
3-Substituted 4-Aryl-5-hydroxyisoxazoles/4-Arylisoxazol-5(4H)-ones 6; General Procedure A (Scheme 6)
General procedure: A solution of 2.5 M n-BuLi in hexane (1.2 equiv) was added dropwise to a solution of HMDS (1.2 equiv) in anhyd THF at -78 °C under argon, and then, after stirring of the mixture for 10 min, a solution of alkyl 2-arylacetate (1 equiv) in THF was added in one portion. The mixture was stirred for 10 min, after which a solution of acyl chloride (1.15 equiv) in THF was added in one portion and the mixture was stirred for 15 min at -78 °C and then overnight at r.t. The reaction mixture was quenched with sat. aq NH4Cl, extracted with EtOAc or Et2O, and the organic layer was washed with brine and dried over Na2SO4. The solvents were evaporated to give 3-substituted alkyl 2-aryl-3-oxopropanoate 5, which was used without further purification. NH2OH·HCl (2-5 equiv) was added to a solution of 5 in MeOH and the mixture was refluxed for 24 h. The solvent was evaporated, the residue was treated with H2O, and the precipitate that formed was filtered, washed with H2O and a mixture of PE/EtOAc (10:1), and then dried in air to give pure 3-substituted 4-aryl-5-hydroxyisoxazole/4-arylisoxazol-5(4H)-one 6. The yields of 6 were calculated for the two steps, and is based on the starting alkyl 2-arylacetate.
With potassium fluoride; 18-crown-6 ether In tetrahydrofuran at 40℃; for 24h; Schlenk technique;
3.2.1. Representative Procedure for the Synthesis of Acyl Fluorides from Acyl Chlorides
General procedure: To a 50 mL of Schlenk tube charged with a magnetic stir bar, were successively added acyl chloride(4.0 mmol), 18-crown-6 (52.9 mg, 0.2 mmol, 5 mol %), KF (2.32 g, 40 mmol, 10 equiv), and THF (20 mL).After the reaction was stirred at 40 °C for 24 h, insoluble inorganic solid (KF or KCl) was filtered,and the volatiles were concentrated using a rotary evaporator. The crude product was purified by bulb-to-bulb distillation to aord the corresponding acyl fluorides 1 [35].
With potassium fluoride; 18-crown-6 ether In tetrahydrofuran at 40℃; for 24h; Schlenk technique; Inert atmosphere;
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